The mesocortical dopamine (DA) pathway is implicated ina the regulation of many important behaviors such as working memory and responses to stressful environmental events. Previous research has shown that this system is regulated differently that the other two major dopaminergic systems of the brain, the mesolimbic and nigrostriatal systems. Such research has primarily concentrated on the regulation of DA neurons by DA D1 and D2 receptor subtypes. However, the regulation of DA efflux by endogenous serotonin (5-HT) may differ between these pathways, explaining findings such as the greater responsiveness of cortical, relative to striatal, DA, following administration of atypical antipsychotic drugs with strong affinities for 5-HT2 receptors. The proposed research will thus examine and contrast the serotonergic versus the dopaminergic regulation of these three pathways. It is hypothesized that 5-HT , via actions on 5-HT2 and/or 5-HT3 receptors, has a more prominent role in the regulation of mesocortical, relative to nigrostriatal, DA release. The specific aims of this proposal will compare the regulation of axonal DA release by 5-HT and DA receptors located in DA cell body regions versus those located in DA nerve terminal areas. These aims will be accomplished by measuring extracellular DA levels in athe intact animal with in vivo microdialysis following administration of specific 5-HT2, 5-HT3, D1, and D2 receptor agonists and antagonists. The effects of systemically administered drugs will be compared to those observed following local administration, through a microdialysis probe, into DA cell body or terminal areas. Additionally, the modulation of impulse-mediated versus carrier-mediated DA release by cortical and striatal 5-HT and DA receptors will be compared in the intact animal. The use of the in vivo rather than the in vitro preparation will permit assessment of 5-HT/DA interactions in a system that is intact with respect to the multiple feedback loops, short and long, that regulate DA release. This research will increase the understanding of somatodendritic and terminal mechanisms regulating mesocortical DA release, the differences between the mesocortical and mesostriatal DA systems, and the serotonergic modulation of DA release. Since abnormalities of the mesocortical DA pathway have been implicated in disorders such as schizophrenia, this research may aid in our understanding of these disorders and in the design of new pharmacotherapeutic agents.